PHARMACOLOGICAL MODULATION OF PEPTIDE GROWTH-FACTOR RECEPTOR EXPRESSION ON TUMOR-CELLS AS A BASIS FOR CANCER-THERAPY

Membrane receptors for peptide growth factor receptors (PGF-R) play a crucial role in the regulation of cancer cell proliferation and may be have as tumor associated antigens (TAA), which are currently regarded as specific targets for immunodetection and immunotherapy of human can cer. PGF-R are often more expressed by tumor cells than by normal coun terparts and, by analogy to TAA, their surface expression may be regul ated by cytokines. Moreover, the biological functions and specific lig ands of most PGF-R are presently well elucidated as opposed to the gre at majority of TAA. PGF-R may, therefore, represent ideal cellular tar gets for at least two different therapeutic approaches: (i) naked or c onjugated monoclonal antibodies and (ii) genetically engineered fusion proteins composed of PGF-R physiological ligands linked to geneticall y modified bacterial toxins. To date, clinical studies based on target ing of receptors for epidermal growth factor and interleukin-2 on tumo r cells have been performed. Information from such studies suggests th at PGF-R as well as TAA targeting strategies are clinically feasible, but that they still have to be optimized. A variety of host and tumor factors which affect targeting of neoplastic cells have been recently identified. For instance, it has been demonstrated that the antigenic density of the targeted molecule at the tumor cell surface is an impor tant factor. In this view upregulation of PGF-R on cancer cells could be of major clinical advantage in immunotargeting. It has been reporte d that several cytokines and chemical compounds can induce PGF-R modul ation on tumor cells. This paper reviews therapeutic opportunities rel ated to the pharmacologic modulation of PGF-R expression. In addition a mechanistic hypothesis regarding PGF-R upregulation induced by cytos tatic drugs and cytokines is proposed.